The ophthalmopathy of Graves' disease is a disfiguring, sight threatening condition of unclear pathogenesis and no specific or definitive therapy. Graves' disease primarily manifests with hyperthyroidism that results from the stimulation of the TSHR by specific autoantibodies that mimic the effect of TSH. Often the ophthalmopathy accompanies the hyperthyroidism. Rather than being considered two separate entities, hyperthyroidism and ophthalmopathy are different manifestations of the same underlying autoimmune process. No spontaneous animal model of Graves' disease exists. Recently, an animal model has been developed in which a proportion of individuals manifest immunological and endocrinological features of Graves' disease. We have generated and extended such mouse model. The overall goal of this proposal is to use this Graves'-Iike animal model to investigate critical issues of Graves' disease as is Graves' ophthalmopathy as follows: 1. Graves' ophthalmopathy in the Graves'-Iike mouse model. New observations suggest the immunizing cells used in the model behave as APC that constitutively express B7-1 molecules and bias the immune response to a Th1 type. These APC also have the capacity of presenting non-specific antigens present in culture medium. With this information we have modified our immunization protocol to improve specific (TSHR) antigen presentation and deviate the immune response to a Th2 type characteristic of human Graves'. We propose to: a. Study the development of Graves' disease/ophthalmopathy in both, Th1 and Th2 settings. b. Examine the role of CD40 for orbital fibroblast-B/T cell cross talk. c. Study the regulation of TSHR in orbital fibroblasts/preadipocytes. 2. Characterize TSHR antibodies in their relationship to Graves' ophthalmopathy.